#14 Functional Senescence of Innate Immunity and Pneumonia Risk in Older Adults.With advancing age, there is a general waning of immune competence collectively termed immune senescence. Previously, immune senescence was felt to primarily affect only the adaptive immune system (e.g. B and T cell responses, delayed typehypersensitivity), the hallmark of which is recognition of specific antigens with memory responses. However, recent data suggest innate immunity is also profoundly affected. Innate immunity does not depend on prior exposure to a specific antigen, but recognizes general patterns of microbial products (e.g. microbial lipoproteins, DNA, peptide sequences). Two important components of innate immunity are profoundly impaired with advanced age, even in the absence of significant co-morbidity. First, phagocytic function (the ability to engulf bacteria) of polymorphonuclear neutrophils (PMNs) is markedly reduced in older adults. This correlates with lower cell surface expression of CD16, an important receptor through which PMNs recognize the Fc portion of immunoglobulin and phagocytose bacteria. Second, very recent animal studies have shown impaired expression of Toll-like receptors (TLRs) and reduced cytokine production after stimulation of TLRs by specific ligands. Human studies are needed to determine if this is true in older humans. Little is known about the relationship between immune senescence, particularly senescent nnate immunity, and the risk of acquiring infections in older adults. The major goals of this proposal are to provide important pilot data to assist in designing of future studies of immune senescence, and to test our general hypothesis that senescent innate immunity contributes to the risk of infection in older adults. Using standard methods of flow cytometry and ELISA cytokine assays within an ongoing study of community-acquired pneumonia (CAP) in older adults, the specific aims are: 1) Determine whether innate and adaptive immune senescence occur in the same individuals or are independent phenomena; 2) Determine the intra-individual variation of innate immune senescence parameters (PMN phagocytosis and CD16 expression, and TLR expression and function) in older adults with and without CAP; and 3) Determine whether there is an association between CAP and senescent innate immunity. These data are essential to design meaningful studies using the case-control method, the most effective means of studying the link between immune senescence and infection risk.